It is now recognized that in addition to its role in the activation of contraction, intracellular calcium modulates many elements of cardiac cellular metabolism. A variety of indirect data have suggested the existence of at least two membrane currents which are regulated by intracellular calcium and which are important in both normal and abnormal cardiac excitation. One of these currents is apparently a potassium current which contributes to setting the normal resting potential, terminating the action potential, and to opposing spontaneous depolarizations. The other current is a rather nonselective current responsible for induced automaticity (transient depolarizations) seen during cardiac glycoside toxicity. In the first series of experiments the dual nature of these currents will be established by taking advantage of their differential sensitivity to intracellular cesium ions. Other experiments will use recently developed methods for measuring currents in isolated myocytes and in cell-free membrane patches. The cell-free patch clamp experiments will identify the kinds of calcium-regulated channels that exist in cardiac cell membranes and characterize them in terms of their ion selectivities and their voltage and calcium sensitivity. Experiments using the intact myocytes will study the role of calcium released from the sarcoplasmic reticulum (SR) in regulating these currents. These experiments will compare currents measured in cell-attached patches during patch depolarizations which do not activate SR calcium release with those obtained during similar depolarizations of the whole cell which do activate SR calcium release. Other experiments will examine the effects of pharmacological agents known to interact with the calcium-dependent regulator protein, calmodulin, to see if this protein or a similar entity might be involved in the regulation of membrane currents in cardiac cells.